EP0759742A1 - Physiologically acceptable emulsions containing perfluorocarbon ether hydrides and methods of use - Google Patents
Physiologically acceptable emulsions containing perfluorocarbon ether hydrides and methods of useInfo
- Publication number
- EP0759742A1 EP0759742A1 EP95920545A EP95920545A EP0759742A1 EP 0759742 A1 EP0759742 A1 EP 0759742A1 EP 95920545 A EP95920545 A EP 95920545A EP 95920545 A EP95920545 A EP 95920545A EP 0759742 A1 EP0759742 A1 EP 0759742A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- emulsion
- ether
- emulsions
- amount
- emulsion according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000839 emulsion Substances 0.000 title claims abstract description 140
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 title claims abstract description 125
- -1 perfluorocarbon ether hydrides Chemical class 0.000 title claims abstract description 75
- 238000000034 method Methods 0.000 title claims description 30
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000001301 oxygen Substances 0.000 claims abstract description 28
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 28
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 12
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 239000002872 contrast media Substances 0.000 claims abstract description 10
- 230000005855 radiation Effects 0.000 claims abstract description 10
- 238000002512 chemotherapy Methods 0.000 claims abstract description 8
- 238000002595 magnetic resonance imaging Methods 0.000 claims abstract description 8
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 8
- 238000005481 NMR spectroscopy Methods 0.000 claims abstract description 7
- 238000007887 coronary angioplasty Methods 0.000 claims abstract description 7
- 238000012984 biological imaging Methods 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 238000002604 ultrasonography Methods 0.000 claims abstract description 6
- 238000002591 computed tomography Methods 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 41
- 150000001875 compounds Chemical class 0.000 claims description 37
- 239000004094 surface-active agent Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 239000003921 oil Substances 0.000 claims description 20
- 235000019198 oils Nutrition 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
- 150000002170 ethers Chemical group 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 210000000056 organ Anatomy 0.000 claims description 14
- 208000006011 Stroke Diseases 0.000 claims description 9
- 238000009835 boiling Methods 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 235000019485 Safflower oil Nutrition 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 235000005713 safflower oil Nutrition 0.000 claims description 6
- 239000003813 safflower oil Substances 0.000 claims description 6
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
- 239000000787 lecithin Substances 0.000 claims description 5
- 235000010445 lecithin Nutrition 0.000 claims description 5
- 229940067606 lecithin Drugs 0.000 claims description 5
- 230000010412 perfusion Effects 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 238000002399 angioplasty Methods 0.000 claims description 4
- 206010053648 Vascular occlusion Diseases 0.000 claims description 3
- 230000002411 adverse Effects 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 230000003204 osmotic effect Effects 0.000 claims description 3
- 210000002966 serum Anatomy 0.000 claims description 3
- 239000003549 soybean oil Substances 0.000 claims description 3
- 235000012424 soybean oil Nutrition 0.000 claims description 3
- 208000021331 vascular occlusion disease Diseases 0.000 claims description 3
- 239000002473 artificial blood Substances 0.000 claims description 2
- 238000003384 imaging method Methods 0.000 claims description 2
- 239000007951 isotonicity adjuster Substances 0.000 claims description 2
- 210000001835 viscera Anatomy 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 8
- 201000010099 disease Diseases 0.000 claims 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 4
- 230000000116 mitigating effect Effects 0.000 claims 4
- 230000002708 enhancing effect Effects 0.000 claims 2
- 230000017531 blood circulation Effects 0.000 claims 1
- 239000003633 blood substitute Substances 0.000 abstract description 10
- 229940039231 contrast media Drugs 0.000 abstract description 7
- 239000002671 adjuvant Substances 0.000 abstract description 5
- 230000002792 vascular Effects 0.000 abstract description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 44
- 238000002360 preparation method Methods 0.000 description 38
- 239000000047 product Substances 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 25
- 239000007858 starting material Substances 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 150000002148 esters Chemical class 0.000 description 14
- 210000004185 liver Anatomy 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 11
- 150000004702 methyl esters Chemical class 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 230000021736 acetylation Effects 0.000 description 10
- 238000006640 acetylation reaction Methods 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 238000004293 19F NMR spectroscopy Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 9
- 239000012346 acetyl chloride Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 238000003682 fluorination reaction Methods 0.000 description 9
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
- 238000006114 decarboxylation reaction Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 150000004678 hydrides Chemical class 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000032050 esterification Effects 0.000 description 6
- 238000005886 esterification reaction Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000006140 methanolysis reaction Methods 0.000 description 6
- 150000004812 organic fluorine compounds Chemical class 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000006845 Michael addition reaction Methods 0.000 description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 150000001242 acetic acid derivatives Chemical class 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- QZCJOXAIQXPLNS-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,4a,5,5,6,6,7,7,8,8,8a-octadecafluoronaphthalene 4-(2-aminoethyl)benzene-1,2-diol Chemical compound NCCc1ccc(O)c(O)c1.FC1(F)C(F)(F)C(F)(F)C2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C2(F)C1(F)F QZCJOXAIQXPLNS-UHFFFAOYSA-N 0.000 description 4
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 150000002894 organic compounds Chemical class 0.000 description 4
- 239000012286 potassium permanganate Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 150000003626 triacylglycerols Chemical class 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 241000220317 Rosa Species 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 239000010685 fatty oil Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000002357 osmotic agent Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical class FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical group CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 2
- 229940043375 1,5-pentanediol Drugs 0.000 description 2
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 2
- MNDIARAMWBIKFW-UHFFFAOYSA-N 1-bromohexane Chemical compound CCCCCCBr MNDIARAMWBIKFW-UHFFFAOYSA-N 0.000 description 2
- YZWKKMVJZFACSU-UHFFFAOYSA-N 1-bromopentane Chemical compound CCCCCBr YZWKKMVJZFACSU-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- GAWAYYRQGQZKCR-UHFFFAOYSA-N 2-chloropropionic acid Chemical compound CC(Cl)C(O)=O GAWAYYRQGQZKCR-UHFFFAOYSA-N 0.000 description 2
- HXDOZKJGKXYMEW-UHFFFAOYSA-N 4-ethylphenol Chemical compound CCC1=CC=C(O)C=C1 HXDOZKJGKXYMEW-UHFFFAOYSA-N 0.000 description 2
- VGVHNLRUAMRIEW-UHFFFAOYSA-N 4-methylcyclohexan-1-one Chemical compound CC1CCC(=O)CC1 VGVHNLRUAMRIEW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- ALQSHHUCVQOPAS-UHFFFAOYSA-N Pentane-1,5-diol Chemical compound OCCCCCO ALQSHHUCVQOPAS-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- DCAYPVUWAIABOU-UHFFFAOYSA-N hexadecane Chemical compound CCCCCCCCCCCCCCCC DCAYPVUWAIABOU-UHFFFAOYSA-N 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- DNZMDASEFMLYBU-RNBXVSKKSA-N hydroxyethyl starch Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O.OCCOC[C@H]1O[C@H](OCCO)[C@H](OCCO)[C@@H](OCCO)[C@@H]1OCCO DNZMDASEFMLYBU-RNBXVSKKSA-N 0.000 description 2
- 229940050526 hydroxyethylstarch Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229910000096 monohydride Inorganic materials 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 125000005460 perfluorocycloalkyl group Chemical group 0.000 description 2
- RVZRBWKZFJCCIB-UHFFFAOYSA-N perfluorotributylamine Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)N(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F RVZRBWKZFJCCIB-UHFFFAOYSA-N 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 239000002888 zwitterionic surfactant Substances 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- OBGZODCYKSYLOI-UHFFFAOYSA-N 1,1,1,3,3,5,5,5-octafluoro-2,2,4,4-tetrakis(trifluoromethyl)pentane Chemical compound FC(F)(F)C(C(F)(F)F)(C(F)(F)F)C(F)(F)C(C(F)(F)F)(C(F)(F)F)C(F)(F)F OBGZODCYKSYLOI-UHFFFAOYSA-N 0.000 description 1
- CMBKOSTZCGEKQA-UHFFFAOYSA-N 1,1,2,2,3,3,4,5,6,7-decafluoroindene Chemical compound FC1=C(F)C(F)=C2C(F)(F)C(F)(F)C(F)(F)C2=C1F CMBKOSTZCGEKQA-UHFFFAOYSA-N 0.000 description 1
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 229940035437 1,3-propanediol Drugs 0.000 description 1
- MMLWQANUZJTBLY-UHFFFAOYSA-N 1-(2,6-dimethylphenoxy)ethanol Chemical compound CC(O)OC1=C(C)C=CC=C1C MMLWQANUZJTBLY-UHFFFAOYSA-N 0.000 description 1
- WKRHHSKAXNEKGY-UHFFFAOYSA-N 1-(2-hexoxyethoxy)ethanol Chemical compound CCCCCCOCCOC(C)O WKRHHSKAXNEKGY-UHFFFAOYSA-N 0.000 description 1
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
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- A—HUMAN NECESSITIES
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Definitions
- This invention relates to physiologically acceptable aqueous emulsions of perfluorocarbon ether hydrides having 8 to 12
- novel emulsions have various medical applications. They are especially useful medically as contrast media for various biological imaging modalities, such as nuclear magnetic resonance, 19 F-magnetic resonance imaging, ultrasound, x-ray, and computed
- perfluorocarbon compounds e.g., perfluorodecalin, perfluoroindane, perfluorotrimethyl bicyclo [3.3.1] nonane, perfluoromethyl adamantane, perfluorodimethyl adamantane, and perfluoro-2,2,4,4-tetramethylpentane; 9-12C perfluoro amines, e.g., perfluorotripropyl amine, perfluorotributyl amine, perfluoro- 1-azatricyclic amines; bromofluorocarbon compounds,
- Neat, highly fluorinated organic compounds are immiscible in blood.
- U. S. Patent 3,991 ,138 discloses perfluorocarbon emulsions as artificial bloods having fluorocarbons that may be excreted from the animal body within a clinically acceptable time period.
- perfluorocyclocarbons were found to leave the animal body at a faster rate than other perfluorocarbons.
- perfluorocarbon ethers were administered to an animal, they were found to reside in the liver and spleen rather indefinitely. More recently, a hydrofluoroalkyl ether,
- emulsions containing perfluorocarbons that function effectively as oxygen transport agents and that may be excreted from the body within a clinically acceptable time period.
- Such emulsions must not only contain a high enough concentration of the highly fluorinated organic compound to be effective at the desired level of oxygen transport, they must also be capable of sterilization, preferably by heat, have long term stability in the fluid or non-frozen state, persist for
- This invention relates to physiologically acceptable aqueous emulsions of perfluorocarbon ether hydrides, particularly
- PFC ether hydride(s) hyd-roperfluoroaliphatic ethers or such ethers substituted with a perfluoroalicyclic group
- medical applications e.g., as contrast media for various biological imaging modalities, including nuclear magnetic resonance, 19 F-magnetic resonance imaging, ultrasound, x-ray, and computed tomography, as oxygen transport agents or "artificial bloods" in the treatment of heart attack, stroke, and other vascular obstructions, as adjuvants to coronary angioplasty and in cancer radiation and chemotherapy.
- biological imaging modalities including nuclear magnetic resonance, 19 F-magnetic resonance imaging, ultrasound, x-ray, and computed tomography
- oxygen transport agents or "artificial bloods" in the treatment of heart attack, stroke, and other vascular obstructions as adjuvants to coronary angioplasty and in cancer radiation and chemotherapy.
- physiologically acceptable emulsions of this invention contain a C 8 to C 12 saturated hydroperfluoroaliphatic ether or such an ether substituted with a perfluoroalicyclic group, or mixtures thereof.
- the aliphatic ether is a straight-chain or branched-chain of carbon atoms.
- the other components of the emulsion include water and a surfactant, where the components are contained in the emulsions in amounts for acceptable physiological administration.
- Especially preferred emulsions contain C 9 to C PFC ether hydrides which have been found to reside for an extremely short time in the essential organs such as the liver.
- the PFC ether hydrides offer a new dimension of synthetic flexibility in the formulation of physiologically acceptable emulsions. These PFC ether hydrides may
- perfluoro such as is the case of “perfluoroaliphatic”, “perfluoroalicyclic”, “perfluoroalkyl”, or “perfluoroalkylene”, means that except as may be otherwise indicated by the prefix "hydro”, there are neither any carbon-bonded hydrogen atoms replaceable with fluorine, nor any unsaturation.
- hydroperfluoroaliphatic ether means there is at least one carbon- bonded hydrogen atom and the remainder of carbon atoms in the aliphatic group are bonded to fluorine or oxygen in the compound. This compound may also be called “perfluoroaliphatic ether hydride”.
- oxygen atoms, or the carbon group is aliphatic, alicyclic or alicyclic- substituted aliphatic, either straight-chain or branched-chain.
- “1 ° hydrogen” or “2° hydrogen” herinafter means the hydrogen atom is bonded to a primary or a secondary carbon atom, respectively.
- the physiologically acceptable aqueous emulsions of this invention contain a C 8 -C 12 PFC ether hydride, water and a surfactant, where the components are contained in the emulsion in amounts for acceptable physiological administration.
- the PFC ether hydride is selected from the group of a saturated C 8 to C 12 hydroperfluoroaliphatic ether, a hydroperfluoroaliphatic ether substituted with a saturated perfluoroalicyclic group, and a hydroperfluorocycloaliphatic ether and mixtures of such ethers.
- These aliphatic ethers have either straight- chain or branched-chain carbon atoms. By “saturated”, it is meant that these compounds have no double bonds or unsaturation in the molecule.
- the emulsions contain a
- ether hydrides have boiling points of at least about 120 * C which render them nontoxic with satisfactory clearance rates from the animal body.
- a preferred class of PFC ether hydrides may be represented by the Formula I:
- H is a primary hydrogen atom or a 2° hydrogen atom on
- X is a fluorine atom, a primary hydrogen atom, or a 2° hydrogen atom on a carbon adjacent to an ether oxygen atom; n is an integer of 0 to 4; and
- R f , R f ' and R f " are independently selected from unbranched or branched groups consisting of perfluoroalkylene, perfluorocycloalkylene, or perfluorocycloalkylene containing one or more ether oxygens.
- Compounds of Formula I in which hydrogen atoms are either primary or secondary and attached to a carbon adjacent to an ether oxygen are preferred because they are easy to prepare and more stable to exposure to base, heat, and oxidative conditions. Therefore, they are more likely to withstand heat sterilization and less likely to be biologically reactive or metabolized.
- a first group of PFC ether hydrides within Formula I which are especially preferred are C 9 -C 10 dihydroperfluorocarbon ethers in which the hydrogen atoms may be 1°, or 2° on a carbon atom adjacent to an ether oxygen. These may be represented by the following compounds which leave the body either within several days or a very short time.
- cyclo-C ⁇ F 11 - or "cyclo-C ⁇ F 10 -"
- a second group of preferred PFC ether hydrides within the scope of Formula I are Cg-C,-, perfluorocycloalkyl- or perfluorocycloalkyl-substituted perfluoroalkylene ether hydrides, as represented by the following compounds which leave the body within several days: cyclo-C 6 F 11 -CF 2 OC 2 F 4 H cyclo-CgF T .-OCjFgH cyclo-C ⁇ F -C 2 F 4 OCF 2 -H p-CF 3 O-cyclo-C ⁇ F 10 -C 2 F 4 -H
- a third class of hydroperfluoroalkyl ethers that are preferred include C 8 -C 10 hydroperfluoroalkyl ethers where the hydrogen atom is 1 ° or is 2° bonded to a carbon atom adjacent to an ether oxygen either bonded to an end carbon or intermediate carbon adjacent to an ether as represented by the following compounds:
- the PFC ether hydrides of this invention typically contain one to five ether oxygen atoms. Preferably, one or two ether oxygens
- ether oxygens are present in the monohydrides and up to 5 ether oxygens are present in the dihydrides.
- the hydrogen atom can in principle be located on any carbon in the compound, we prefer, when there is more than one such hydrogen, that they be on different carbons (i.e., not geminal).
- a hydrogen is located at opposite ends of the carbon chain.
- diomegahydro perfluoroalkyl ethers are sometimes referred to herein as "diomegahydro" perfluoroalkyl ethers.
- any of the PFC ether hydrides of this invention may be mixed together or with other well known highly fluorinated organic compounds and used in the emulsions of this invention.
- such emulsions may comprise
- the emulsions of this invention comprise from about 10% to about 50% (by volume) of the PFC ether hydride, and, most preferably, at least about 40% (by volume).
- the PFC is present in as high a volume concentration as possible, e.g., 40% by volume is often preferred because that concentration matches the approximate oxygen content capacity of whole blood.
- emulsions of this invention are made using conventional means and methods and include components common to
- surfactants useful in the emulsions of this invention are any of the known anionic, cationic, nonionic and zwitterionic surfactants.
- Fluorinated surfactants e.g., ATSURF ® F-31 (ICI, Wilmington, DE), may also be used in the emulsions of this invention. See, e.g., Riess et al., "Design, Synthesis And Evaluation Of Fluorocarbons And Surfactants For In Vivo Applications, New
- mixtures of compounds one or more of which are not surfactants, but which compounds when combined act as surfactants, may also be usefully employed as the surfactant component of the emulsions of this invention.
- compositions may be generally referred to herein as emulsions, it should be understood that they may be considered solutions, micellar solutions, microemulsions, vesicular suspensions, or mixtures of all of these physical states. Accordingly,
- the surfactants used in the emulsions of this invention are physiologically acceptable, for example, preferably one or more of
- oleic acid such as sodium oleate.
- lecithin oleic acid
- the amount of a particular surfactant used in the emulsions of this invention depends on the amounts and properties of the other components of the emulsion, typically we employ between about 0.5 and 10% (by weight of the total emulsion) of surfactant. More
- the emulsions of this invention may also contain an oil that is not substantially surface active and not significantly water soluble.
- oils are, for example, described in EP 231 ,091 , WO 89/10118 and U.S. Pat. 4,866,096. They include liquid fatty oils, hydrocarbons, waxes, such as monoesters of a fatty acid and a monohydroxide alcohol, long chain ethers, diglycerides, triglycerides, silicone oils and nitriles.
- oils in these classes are palmitoyl oleate, octyl nitrile, dodecyl nitrile, soybean oil, safflower oil, mineral oil, hexadecane, and diglycerides and triglycerides having a C-
- any mixture of triglycerides and or oils that are similar in fatty acid composition to triglycerides may be used.
- oils may be used singly or in various combinations in the emulsions and processes of this invention.
- the oil or combination of oils must, of course, be physiologically acceptable liquid fatty oils, such as soybean and safflower oils.
- the amount of oil, or oils, if present, in the emulsions of this invention may vary over a wide range of concentrations depending on the concentration of oil, or oils, if present, in the emulsions of this invention.
- the emulsions of this invention may also contain other components conventionally used in "artificial bloods" or blood
- emulsions according to this invention usually also contain an isotonic agent, typically sugars, such as glucose, mannose and fructose, glycerin, or other polyhydric alcohols to adjust the osmotic pressure of the emulsion to about that of blood. Osmolarity may also be adjusted after sterilization by buffers such as sodium chloride, sodium bicarbonate
- bicarbonate, magnesium chloride, and the like to reduce the possibility of red blood cell injury.
- other amounts and other osmotic pressure controlling agents, e.g., Tyrode solution could as well be used.
- these osmotic pressure controlling agents e.g., Tyrode solution
- emulsions may be mixed with 0.9% saline, lactated Ringer's solution, and serum and serum products with no adverse effect on emulsion particle size and stability.
- the emulsions of this invention may also include other components, such as osmotic agents, e.g., dextran or hydroxyethyl-starch (HES), and antioxidants.
- osmotic agents e.g., dextran or hydroxyethyl-starch (HES)
- HES hydroxyethyl-starch
- the PFC ether hydride is C 8 -C 10
- the surfactant is egg yolk lecithin
- the oil, if present, is safflower oil.
- Glycerin is typically added to the emulsion to adjust isotonicity.
- the PFC ether hydride is present in about 40% by volume, the lecithin in about 2.0 w/v%, and the safflower oil, if present, in about 2.0 v/v% of the emulsion.
- the emulsions of this invention are useful as contrast media by various biological imaging modalities, e.g., nuclear magnetic resonance, 9 F-magnetic resonance imaging,
- the emulsions are useful as contrast agents and for direct imaging in
- the emulsions of the invention may be administered, for example, by bolus, orally, subcutaneously, intraperitoneally, intrathecally, or other medically approved method of
- the emulsions of this invention may also be used as artificial bloods and infused intraveneously to animals or humans suffering from blood loss or oxygen depleted blood. Besides the utility of such artificial bloods for animals and humans, these emulsions can be used as a perfusate for the preservation of internal organs, such as with organ transplants, for extended periods outside the body. Publications demonstrating the usefulness of highly fluorinated organic compound-containing emulsions to preserve organs outside the body
- the emulsions of this invention may be prepared by conventional mixing of the perfluoroalkyl ether hydrides fluorinated components (discontinuous phase) with an aqueous (continuous) phase and a surfactant.
- the emulsions of this invention may be prepared by mixing an aqueous phase with any suitable surfactant, and optionally, osmotic agents, buffering agents, electrolytes if desired,
- emulsifying agents such as sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite
- emulsions of this invention may also be prepared by pre-mixing an aqueous dispersion with any suitable surfactant(s) and,
- the oil may then be mixed into the above-described aqueous dispersion at a predetermined rate.
- the perfluoroalkyi ether hydrides may then be mixed in at a predetermined rate so as to provide an emulsion of this invention.
- the resulting emulsion is sterilized, preferably at temperatures in excess of 115°C, more preferably at about 121°C, packaged and otherwise processed for storage and use.
- the mixing, pre-mixing if desirable, and emulsification of the components may be done using any of the conventional mixers, homogenizers, and emulsifiers.
- one may employ Fisher brand touch mixers and microfluidizers or Gaulin homogenizers.
- an inert atmosphere e.g., N 2
- N 2 an inert atmosphere
- the organic starting material C 8 H 17 -O-C 2 H 4 CO 2 CH 3 , was prepared by base-catalyzed Michael addition of n-octanol to
- the methyl ester was directly fluorinated with F 2 to produce the fluorinated ester, C 8 F 17 -O-C 2 F 2 CO 2 CF 3 .
- This fluorination was carried out in a 2-liter, jacketed reactor vessel of MonelTM metal equipped with a magnetic drive agitator, gas feed line, organic reactant feed line, and a reflux condenser.
- the gas feed line was 0.3 cm diameter tube reaching to a point below the bottom impeller of the agitator.
- the feed line was a 0.15 cm diameter tube connected to a syringe pump.
- the reflux condenser consisted of about 6 meters of two coiled concentric tubes, the inner tube having a 1.27 cm diameter and the outer tube having a 2.54 cm diameter. Gases from the reactor were cooled in the inner tube by refrigerant, ethylene glycol-water, flowing in the annulus
- the reactor was charged with about 1.8 liters of FreonTM 113 chlorofluorocarbon and purged with 650 ml/min of
- glycol was prepared in a 3 L round-bottom flask. 1000 g of the C 8 F 17 OC 2 F 4 -CO 2 H was added dropwise to the stirred KOH solution. Upon complete addition, an additional 10 g of KOH was added and the mixture heated. The fluorochemical product of decarboxylation was distilled together with a small amount of water from the neutralization of the acid. The lower fluorochemical phase of the distillate was separated, washed with salt water, dried over Na 2 SO 4 and distilled as in Example 1 to yield 817 g of C 8 F 17 -O-C 2 F 4 H.
- C 7 H 15 -O-C 2 H 4 CO 2 CH 3 was prepared by base-catalyzed Michael addition of n-heptanol to acrylonitrile, followed by acid- catalyzed methanolysis. 550 g of the corresponding methyl ester, C 7 F 15 -O-C 2 F 4 COOCH 3 , (prepared by essentially the same fluorination and methanolysis procedures of Example 1 ), was added dropwise to a solution of 166.6 g of KOH in approximately 880 ml of ethylene glycol.
- the fluorochemical product was recovered essentially as in Example 1 to yield 440 g which was distilled through a six-plate Snyder column and the fraction boiling from 130 to 131 °C was collected (340 g).
- Example 2 Treatment of the resulting fluorinated product with 30 ml of a 10 weight percent solution of H 2 SO 4 in H 2 0 and shaking at room temperature for 2 hours, filtration of solid fluorinated adipic acid, separation of the F-113 layer, drying over MgSO 4 , and distillation produced a main cut of 73.4 g, b.p. 116°C/20 torr, 96% pure C 4 F 9 -O-(CF 2 ) 5 COOH.
- Example 9 Preparation of H(CF 2 ) 4 -0-(CF 2 ) 4 H from CI(CF,y ⁇ -(CF.-.) 1 CI CI-(CH 2 ) 4 -0-(CH 2 ) 4 -CI was fluorinated as in Example 1 to provide CI(CF 2 ) 4 -0-(CF 2 ) 4 CI. A mixture of 30.3 g CI(CF 2 ) 4 -0-(CF 2 ) 4 CI,
- Example 1 Preparation of C ⁇ F 13 -0-CF 2 CF 2 H from C_F 13 _0 I C 2 F 4 CO 2 H
- the resulting mixture was then heated to 100°C and its pH adjusted to a pH greater than 7 by the addition of 5 g of 45 wt% aqueous KOH. Decarboxylation was carried out by distillation of the resulting mixture. The lower fluorochemical phase of the resulting distillate was separated therefrom, washed with an equal volume of water, and distilled at 123-126°C to give 155 g of a product (99.7% purity). The product was treated with KMnO 4 in acetone to give cyclo-CeF, , CF 2 -O-C 2 F 4 H.
- the starting material, C ⁇ H 13 -0-C 5 H 10 -OC(O)CH 3 was prepared by monoalkylation of 1 ,5-pentanediol with hexyl bromide,
- the starting material, C ⁇ H 13 -0-C 4 H 8 -OC(O)CH 3 was prepared by monoalkylation of 1 ,4-butanediol with hexyl bromide,
- the starting material was prepared by monoalkylation of 1 ,5-pentanediol with pentyl bromide, followed by acetylation with acetyl chloride. This compound was
- Example 1 to give The methyl ester was saponified using excess NaOH, and decarboxylated and distilled essentially as in Example 16. Distillation through a twelve-plate packed glass column gave pure b.p. 125°C. The structure was confirmed by 19 F-NMR.
- the precursor, C 8 H 17 0CH 2 OC 4 H 8 OH was prepared by monoalkylation of butane diol with octyl chloromethyl ether.
- the precursor was first acetylated with acetyl chloride in methylene chloride containing triethylamine and then fluorinated.
- methyl 3-(4-ethoxyphenyl)-trans-2- propenoate was prepared by condensation of 4-ethoxybenzaldehyde with malonic acid, followed by esterification. This methyl ester was fluorinated, methanolized and decarboxylated essentially as in Example 1 to produce the perfluorinated ether hydride.
- the starting material was prepared by condensation of 2,2-diethyl propane diol with dimethyl 3-oxoglutarate. This dimethyl ester was fluorinated, methanolyzed to the diester, and decarboxylated as in Example 1 to produce the perfluorinated ether dihydride.
- the starting material was prepared by reaction of 2,6-
- the starting material was prepared by the treatment of 2-
- the starting material was prepared from the addition of
- Example 25 Preparation of C 7 F 15 OCHFCF 3 from C 7 H 1 _OCH(CH CQ.,CH ?
- the starting material was prepared by the addition of 2- chloropropionic acid to n-heptanol and aq. sodium hydride, followed by esterification to the methyl ester. This ester was fluorinated and decarboxylated as in Example 1 to produce the perfluorinated ether hydride, b.p. 130°C.
- the starting material was prepared by the addition of dichloroacetic acid to sodium butoxide in n-butanol and subsequent acidification in butanol. This ester was fluorinated, methanolyzed and decarboxylated as in Example 1 to produce the perfluorinated ether hydride.
- the starting material was prepared by the addition of 2- bromobutyric acid to n-heptanol and sodium hydroxide, followed by esterification with methanolic HCI. This ester was fluorinated, methanolyzed and decarboxylated as in Example 1 to produce the perfluorinated ether hydride.
- Example 28 Preparation of C 5 F 1 l OCF 2 C(CF 3 ) 2 CF 2 H from C_H 1 ⁇ CH-CtCH-t H I
- the starting material was prepared as described U.S.S.N
- Example 29 Preparation of (C 4 F 9 O)2CFCF2H from (C-H -hCHCH I
- the starting material was prepared by the additon of n- butanol to 2-chloroacetaldehyde and was fluorinated as in Example 1 followed by Raney Ni reduction of the chloride as described in Example
- the starting material was prepared by monoalkylation of
- the starting material was prepared by monoalkylation of ethylene glycol with n-nonyl bromide, followed by acetylation with acetyl chloride. This acetate was fluorinated, hydrolyzed and -37- decarboxylated as in Example 1 to produce the perfluorinated ether hydride, distilling at 153-155°C.
- Example 32 Preparation of (iso-C 3 F 7 ) 2 CFOC 2 F 4 H from (iso-C 6 H-,) ; ,CHOC :; H O.,CH 1
- the starting material was prepared by Michael addition of 2,4-dimethyl-3-pentanol to acrylonitrile followed by methanolysis to the methyl ester. This ester was fluorinated, hydrolyzed and decarboxylated as in Example 1 to produce the perfluorinated ether hydride.
- Example 33 Preparation of C 7 F 15 OCHFCF 3 from C ? H, _OCH(CH CO-,CH ?
- the starting material was prepared by addition of 2- chloropropionic acid to n-heptanol and sodium hydroxide, followed by esterification with methanolic HCI. This was fluorinated as in Example 1 , then treated with pyridine to produce C 7 F 15 OCF(CF 3 )CO 2 F with loss of COF 2 .
- This acid fluoride was decarboxylated as in Example 1 by addition to KOH in ethylene glycol and subsequent heating. The product was formed at a pot temperature of 126°C and was collected by distillation b.p. 130°C.
- Example 34 Preparation of
- the starting material was prepared by the alkylation of 4- ethylphenol with methyl chloroacetate. This ester was fluorinated, hydrolyzed and decarboxylated as in Example 1 to produce the perfluorinated ether hydride, b.p. 131 °C.
- the starting material was prepared by the addition of
- Emulsions were prepared using PFC ether hydrides (PFEH) above identified. According to this general procedure, a crude emulsion of 2 w/v% egg yolk lecithin, 2 v/v% safflower oil, 40 v/v%
- PFEH and water under an inert atmosphere was prepared by mixing at high speed in a Waring blender for about two minutes.
- Rats were then sacrificed at each of several time
- the amount of fluorochemical was assayed in the organs by grinding the tissue in a TissuemizerTM, extracting with carbon
- TIME PTS means the percent of dose present in the liver as recorded after 2 days, 16 days and 30 days post infusion. The percent of dose equals the percent of the total PFEH amount infused in the rats.
- the C 9 -C 10 di-omegahydroperfluorocarbon diethers as a group have the exceptional properties of clearance from the essential organs such as the liver very rapidly, even in a matter of days.
- the C 9 di- omegahydroperfluorocarbon diether cleared the liver immediately or only 2.3% was detectable after two days.
- C 9 -C 10 monohydroperfluoroalkyl monoether or diether compounds are represented by the remaining compounds of the Table, for example, compounds 8-16.
- compound 9 of the Table after 16 days, only 10.5% of the dose of the PFC ether hydride remained in the liver.
- the hydrogen atom of the PFC ether hydrides may be bonded at the end or omega carbon atom of the
Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US08/246,962 US5476974A (en) | 1994-05-20 | 1994-05-20 | Omega-hydrofluoroalkyl ethers, precursor carboxylic acids and derivatives thereof, and their preparation and application |
US246962 | 1994-05-20 | ||
US437299 | 1995-05-17 | ||
US08/437,299 US5502094A (en) | 1994-05-20 | 1995-05-17 | Physiologically acceptable emulsions containing perfluorocarbon ether hydrides and methods for use |
PCT/US1995/006327 WO1995031965A1 (en) | 1994-05-20 | 1995-05-19 | Physiologically acceptable emulsions containing perfluorocarbon ether hydrides and methods of use |
Publications (2)
Publication Number | Publication Date |
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EP0759742A1 true EP0759742A1 (en) | 1997-03-05 |
EP0759742B1 EP0759742B1 (en) | 1998-10-28 |
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EP95920545A Expired - Lifetime EP0759742B1 (en) | 1994-05-20 | 1995-05-19 | Physiologically acceptable emulsions containing perfluorocarbon ether hydrides and methods of use |
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US (2) | US5502094A (en) |
EP (1) | EP0759742B1 (en) |
JP (1) | JPH10500689A (en) |
AU (1) | AU2596695A (en) |
CA (1) | CA2188872C (en) |
DE (1) | DE69505657T2 (en) |
RU (1) | RU2159610C2 (en) |
WO (1) | WO1995031965A1 (en) |
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1995
- 1995-05-17 US US08/437,299 patent/US5502094A/en not_active Expired - Lifetime
- 1995-05-19 EP EP95920545A patent/EP0759742B1/en not_active Expired - Lifetime
- 1995-05-19 JP JP7530433A patent/JPH10500689A/en not_active Withdrawn
- 1995-05-19 RU RU96122883/14A patent/RU2159610C2/en not_active IP Right Cessation
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- 1995-05-19 DE DE69505657T patent/DE69505657T2/en not_active Expired - Fee Related
- 1995-05-19 WO PCT/US1995/006327 patent/WO1995031965A1/en active IP Right Grant
- 1995-05-19 AU AU25966/95A patent/AU2596695A/en not_active Abandoned
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See references of WO9531965A1 * |
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WO1995031965A1 (en) | 1995-11-30 |
EP0759742B1 (en) | 1998-10-28 |
US5502094A (en) | 1996-03-26 |
US5567765A (en) | 1996-10-22 |
DE69505657T2 (en) | 1999-07-15 |
JPH10500689A (en) | 1998-01-20 |
RU2159610C2 (en) | 2000-11-27 |
CA2188872A1 (en) | 1995-11-30 |
DE69505657D1 (en) | 1998-12-03 |
AU2596695A (en) | 1995-12-18 |
CA2188872C (en) | 2008-09-16 |
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